key: cord-0837174-zak1tzt0 authors: Miao, Yi; Fan, Lei; Li, Jian-Yong title: Potential Treatments for COVID-19 Related Cytokine Storm - Beyond Corticosteroids date: 2020-06-16 journal: Front Immunol DOI: 10.3389/fimmu.2020.01445 sha: 3dc880a6b085d1de79240ad6397c6ff121c291d9 doc_id: 837174 cord_uid: zak1tzt0 nan Corticosteroids could be used to suppress the cytokine storm and have been used in some patients (1) . However, based on the evidence from patients with MERS and ARDS, the use of corticosteroids did not provide a survival benefit but rather delayed the clearance of the virus, therefore, the systemic use of corticosteroids is not recommended by the WHO guidance (1) . As a result, alternatives for dampening the overwhelming cytokine release are required. As we know, the cytokine storm also occurs in other settings. In patients with leukemia or lymphoma who receive chimeric antigen receptor (CAR) T cells therapy, cytokine release syndrome (CRS) occurs during and after the infusion of CAR T cells (8) . In patients receiving CAR T cells therapy, those with CRS had elevated concentrations of interferon γ, tumor necrosis factor α, interleukin (IL)-1B, IL-2, IL-6, IL-7, IL-8, IL-10, IL-12, granulocyte macrophage colony stimulating factor (GM-CSF), and macrophage inflammatory protein (MIP)-1. The cytokine profile in CRS related to CAR T cells infusion is similar to that in cases of SARS-CoV-2 infection. The anti-IL-6 receptor antibody tocilizumab is effective in controlling CAR T cells infusion related CRS (response rate: 53-69%) (9) . The above evidence provides us with a rationale for using tocilizumab to manage the cytokine storm in patients with SARS-CoV-2 infection. Another rationale for using tocilizumab to treat COVID-19 is that IL-6 does not enhance the antiviral immunity but decreases the antiviral immunity in patients with COVID-19. Diao et al. found that serum IL-6 was negatively correlated with T cell numbers (10). Mazzoni et al. found that the elevation of IL-6 serum levels was associated with the impairment of cytotoxic activity in patients with COVID-19, and the use of tocilizumab restored the cytotoxic potential of NK cells (11) . Some studies involving off-label use of tocilizumab have shown the potential efficacy of this drug in the treatment of COVID-19 (12) (13) (14) (15) . Another potential drug that could be considered to treat cytokine storm is etoposide, which is used to deplete monocytes and suppress cytokine release in hemophagocytic lymphohistiocytosis (HLH) (16) . It needs to be mentioned that, in SARS-CoV-infected mice, inflammatory monocytemacrophage responses were involved in causing lethal pneumonia, suggesting the importance of suppressing monocytemacrophage system in treating severe pneumonia related to SARS-CoV (17) . The hyperactivation of monocytes/macrophages has been described in patients with COVID-19. Single-cell analysis of bronchoalveolar fluid revealed significantly increased proportions of mononuclear phagocytes in patients with COVID-19, especially those with severe disease. In patients with severe disease, these mononuclear phagocytes showed a predominance of inflammatory monocyte-derived macrophages (18) . These macrophages could not only contribute to acute inflammation but also promote fibrosis generation. Additionally, a significant increase of CD14 + CD16 + monocytes was also detected in patients with severe COVID-19 (19) . These CD14 + CD16 + monocytes expressed IL-6 and caused the acceleration of the inflammation. Therefore, etoposide could be used to inhibit the hyperactivation of monocytes/macrophages to suppress the overwhelming inflammation and ameliorate the pulmonary fibrosis. Other potential drugs for treating cytokine storm include the JAK1/2 inhibitor ruxolitinib, which is effective in inhibiting monocyte activation and cytokine release in patients with HLH (20) . A prospective randomized study has shown the promising efficacy of ruxolitinib in the treatment of severe COVID-19 (21) . In this trial, the ruxolitinib group showed a significant decrease of levels of 7 cytokines compared to the control group, suggesting ruxolitinib suppress the cytokine storm in patients with severe COVID-19. Patients in the ruxolitinib group also had a faster chest CT improvement and a faster recovery from lymphopenia. Ruxolitinib was also well-tolerated in patients with severe COVID-19, indicating ruxolitinib could be safely used to treat patients with COVID-19 (21) . Additionally, therapeutic plasma exchange can reduce the plasma cytokine concentrations rapidly, and has been successfully used to treat HLH and CRS related to CAR T cells infusion (22, 23) , suggesting plasma exchange may be a reasonable option for severe patients with cytokine storm. In a preliminary study, therapeutic plasma exchange reduced the plasma IL-6 level and improved the oxygenation status in patients with severe COVID-19 who had ARDS (24) . Although we admit that supportive care and antiviral therapy remain the mainstay for treating patients with COVID-19, we recommend that treatments for controlling cytokine storm including tocilizumab, etoposide, ruxolitinib, and plasma exchange should be considered in selected COVID-19 patients with cytokine storm. Some pilot studies have shown promising results. Some other treatments may also be effective in controlling the cytokine storm. More randomized clinical trials are needed to evaluate if these treatments could reduce the mortality of patients with COVID-19. YM, LF, and J-YL drafted the manuscript. All authors contributed to the article and approved the submitted version. 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